Process for the manufacture of a solid pharmaceutical administration form

ABSTRACT

The present invention relates to a process for the preparation of a solid pharmaceutical administration form using a 3D printing process as well. The process is a printing process that allows the production of solid pharmaceutical administration forms in a flexible manner and in conformity with the high quality standards required for the production of pharmaceuticals.

The present invention relates to a process for the preparation of asolid pharmaceutical administration form using a 3D printing process aswell. The process is a printing process that allows the production ofsolid pharmaceutical administration forms in a flexible manner and inconformity with the high quality standards required for the productionof pharmaceuticals.

It is believed that future improvements in disease treatment is drivenby point-of-care and home-based diagnostics linked with genetic testingand emerging technologies such as proteomics and metabolomics analysis.This has led to the concept of personalized medicine, which foresees thecustomization of healthcare to an individual patient.

Medication can be applied to the patient by using differentpharmaceutical formulations that are adapted to the desired applicationmethod, for example to oral (including buccal or sublingual), rectal,nasal, topical (including buccal, sublingual or transdermal), vaginal orparenteral (including subcutaneous, intramuscular, intravenous orintradermal) application. In general, oral application is preferred assuch application is easy and convenient and does not cause any harm thatmay be associated with other application methods such as parenteralapplication.

Pharmaceutical formulations usable for oral administration are, forexample, capsules or tablets; powders or granules; solutions orsuspensions in aqueous or non-aqueous liquids; edible foams or foamfoods; or oil-in-water liquid emulsions or water-in-oil liquidemulsions.

Tablets for oral administration are by far the most common dosage form,and are generally prepared by either single or multiple compressions(and in certain cases with moulding) processes. Tablets are usuallyprepared by using multiple process steps such as milling, sieving,mixing and granulation (dry and wet). Each one of these steps canintroduce difficulties in the manufacture of a medicine (e.g., drugdegradation and form change), leading to possible batch failures andproblems in optimization of formulations.

Tablets are almost universally manufactured at large centralized plantsvia these processes using tablet presses essentially unchanged inconcept for well over a century. This route to manufacture is clearlyunsuited to personalized medicine and in addition provides stringentrestrictions on the complexity achievable in the dosage form (e.g.,multiple release profiles and geometries) and requires the developmentof dosage forms with proven long-term stability.

Use of 3D printing technology was proposed as an alternative approach toprovide dosage forms as this potentially allows manufacture ofpersonalized medicines at the point of care (Khaled S. A. et al.:Desktop 3D printing of controlled release pharmaceutical bilayertablets, Int J Pharm 461 (2014) 105-111). Khaled et al. describes theprinting of guaifenesin tablets by using an extrusion based 3D printer.According to this method a water based HPMC gel is prepared, filled intothe printer head of an extrusion based 3D printer and printed. In suchprinting process a multitude of layers are placed successively on top ofeach other thereby forming the tablet. However, use of a gel like HPMCgel to prepare tablets is only feasible with active pharmaceuticalingredients (APIs) that are compatible with and stable in aqueousenvironment. Further, the solvent, especially the water that is presentin the gel, has to be removed after printing which slows down theprocess flow. In addition, change of manufacturing from a tablet havingas specific API to a different tablet with a different API requiresextensive cleaning operations and extends setup times, especially assuch manufacturing process has to meet the high quality standards (GoodManufacturing Practice (GMP)) that are compulsory in the manufacturingof medicinal products.

Katstra W. E. et al. discloses 3D printing of a tablet using a so-calledsolid freeform fabrication (SFF) technique which employs powderprocessing wherein the tablet is build-up in a layer-wise manner(Katstra W. E. et al.: Oral dosage forms fabricated by Three DimensionalPrinting, J Contr Rel 66 (2000) 1-9). The process uses a 3D printercomposed of a pair of horizontal X-Y axes that are suspended over avertical piston, providing control over three directions of motion. Formanufacture of tablet a thin layer of powder is spread onto a pistonplate, droplets of a liquid binder solution are distributed over thepowder bed through a nozzle that is moved back and forth and whichprovides binding of the powder particles together and generation of a 2Dpattern. After lowering the piston by a fixed distance, another thinlayer of powder is spread, and the process is repeated. The processdescribed by Katstra et al. also requires a drying step to remove theliquid that has entered the formulation by the addition of bindersolution which slows down the process flow. Further, the mechanicalproperties of the solid dosage forms, such as friability, might becritical in view of that the particles of the powder contained thereinare only attached to each other by means of a binder and no compressionstep as it is used in conventional tableting processes is involved. Inaddition, change of manufacturing from a tablet having as specificactive pharmaceutical ingredient (API) to a different tablet with adifferent API requires extensive cleaning operations to avoid crosscontamination, especially in view of the formation of dust. To fulfillthe compulsory high quality standards (Good Manufacturing Practice(GMP)) extended setup times are associated with such process.

Goyanes A. et al. describes 3D extrusion printing of a tablet using drugloaded into a polymer (Goyanes A. et al.: Fused-filament 3D printing(3DP) for fabrication of tablets International, J Pharm 476 (2014)88-92). In such method extruded filmaments of polyvinyl alcohol (PVA)are loaded with fluorescein sodium as model drug by incubation in anethanolic fluorescein solution for 24 hours, dried in an oven andsubsequently melt extruded in a 3D printer at 220° C. However, theloading of PVA with API is time consuming, limits its applicability forAPIs with different physicochemical properties and does not allowpreparation of filaments with high contents of API and finally notablets with high drug content. In fact, the diffusion driven loadingstep requires that the API must fulfill specific properties in terms ofsolubility and molecular size to be a suitable subject for such process.Further, the API must have a good thermal stability to be not destroyedat the high extrusion temperature (220° C.). As a result such process isapplicable to a very limited number of APIs only, which are applied tothe patient in low doses and that meet the very specific physicochemicalproperties described above.

WO 2014/188079 discloses manufacturing of oral dosage forms ofvitamin(s) and/or dietary mineral(s) or nicotine by inkjet printing.APIs are dissolved in mixtures of water and alcohols (propylene glycol,glycerol, ethanol), filtered and printed in squares of 1 cm×1 cm onpaper using an inkjet printer. However, such dosage forms are rather twodimensional which is difficult to be handled by and administrated to thepatient compared to three dimensional tablets. Further, due to the lowmass of the dosage form, only dosage forms that contain very low dosagescan be produced. In addition, the APIs must be soluble and stable inwater/alcohol solutions.

All 3D printing processes that are described for the preparation oftablets and that are in principle usable for decentralized production ofpersonalized solid dosage forms exhibit several disadvantages thathinder their broad applicability. Therefore, there is a strong demandfor a process that overcomes such disadvantages. Especially a process isneeded that is fast, that is applicable to a broad range of APIs interms of their physicochemical properties and that is applicable also toAPIs that are administrated to the patient in high dosage ranges(hundreds of milligrams to grams).

A process that meets such criteria is made available by the presentinvention.

The present invention is directed to a process for the manufacture of asolid pharmaceutical administration form comprising an active ingredientcomprising the steps

(a) spreading a powder comprising a fusible material and an activeingredient across the manufacturing area to create a powder bed;

(b) jet printing a fluid comprising an energy absorbing material ontothe powder;

(c) irradiating the powder to induce heating of the energy absorbingmaterial in the powder and thereby to induce melting and fusing of thefusible material present in the powder;

(d) spreading a layer of powder onto the surface of unfused and fusedpowder and subsequently performing step (b) and step (c);

(e) repeating step (d) as often as needed to build up the solidpharmaceutical administration form;

(f) separating the solid pharmaceutical administration form from thepowder bed.

The process can be run on a 3D printer composed of a pair of horizontalX-Y axes that are suspended over a vertical piston, providing controlover three directions of motion and that is equipped with jet head asknown from ink jet printing technology. Preferably the jet headcomprises a multichannel nozzle that allows printing of multiple fluidssuccessively or in parallel. For manufacture of solid pharmaceuticaldosage form is spread onto a mounting plate to create a powder bed, thefluid is precisely distributed over predefined areas of the powder bedthrough a jet head that is moved over the powder bed. By irradiation ofthe powder bed the fusible material is at least partially fused therebygenerating a 2D pattern. After lowering the mounting plate by a fixeddistance, a layer of powder is spread, and the process is repeated.Instead of lowering the mounting plate the spreading means can be raisedby a fixed distance.

The term “solid pharmaceutical administration form” as used herein meansany pharmaceutical formulation that is solid and provides a dosage unitof an active pharmaceutical ingredient that can be administered to apatient by any way of application such as oral, rectal, vaginal,implantation. The solid pharmaceutical administration form can have anyshape adapted to the application requirements, e.g. round, oval, rodlike, torpedo shaped etc. Examples of solid pharmaceuticaladministration forms are tablets, pills, caplets, suppositories,implants.

The term “active ingredient” as used herein means any ingredient thatprovides a pharmacological or biological effect when applied to abiological system. The active ingredient may be a pharmaceutical drug,biological matter of viral or ling origin. Examples of an activeingredient that may be used in the process of the present inventions areinsulin, heparin, calcitonin, hydrocortisone, prednisone, budesonide,methotrexate, mesalazine, sulfasalazine, amphotericin B, nucleic acids,or antigens (peptides, proteins, sugars, or other substances that formsurfaces recognized by the immune system, either produced, extracted, orhomogenized from tissue, an organism or a virus).

The term “spreading” as used herein means a process where a planar layerof powder is applied to a planar ground. Spreading of powder can beachieved by using means that are suitable to create a planar layer ofpowder. Examples of such means are a doctor blade or a roller that canbe moved in parallel to planar ground such as a mounting area or anexisting powder layer to distribute the powder from a reservoir acrossthe planar ground. By the use of a roller a certain level of compactioncan be obtained, which may be advantageous for the manufacture of thesolid pharmaceutical dosage form.

The term “fusible material” is a material that melts and fuses uponheating. The fusible material has a rather low melting point or glasstransition temperature to keep the operation temperature low and to keeppotential detrimental effects on the solid pharmaceutical dosage form,especially the active ingredient, as low as possible but it has to behigh enough to assure stability of the shape of the solid pharmaceuticaldosage form under usual storage conditions, e.g. room temperature.Preferably, the glass transition temperature would be at least 20° C.higher than the projected storage condition at the same humidity. Asuitable range of melting points or glass transition temperatures wouldbe 50-150° C., more preferably 50-100° C., most preferably 60-80° C.Examples of fusible materials are lipids, incl. fats and waxes,derivatives thereof; resins; low melting sugars and sugar alcohols,incl. fructose, sorbitol, xylitol; mixtures of these to reduce meltingpoint; modified sugars such as sucrose esters, sorbitan esters; vitaminE TPGS; pharmaceutical polymers with or without plasticizer (incl.water) with sufficiently low melting point or glass transitiontemperature, incl. PEG/PEO, PEO esters and ethers, PVAc, PVP, PCL,Poloxamers, PVPVA, celluloses and derivatives thereof, poly-acrylates,poly-methacrylates, PLA, PLGA, gelatin, alginate, shellac, agar;

composites, mixtures and blends thereof.

As used herein, “fusing” means complete fusing or partial fusing. Asused herein “melting” means complete or partial melting.

As used herein, “a” or “an” shall mean one or more. As used herein whenused in conjunction with the word “comprising,” the words “a” or “an”mean one or more than one. As used herein “another” means at least asecond or more. Furthermore, unless otherwise required by context,singular terms include pluralities and plural terms include thesingular.

As used herein, “about” refers to a numeric value, including, forexample, whole numbers, fractions, and percentages, whether or notexplicitly indicated. The term “about” generally refers to a range ofnumerical values (e.g., +/−1-3% of the recited value) that one ofordinary skill in the art would consider equivalent to the recited value(e.g., having the same function or result). In some instances, the term“about” may include numerical values that are rounded to the nearestsignificant figure.

As used herein, “jet printing” refers to a process where a fluid isdistributed to the powder bed by ejecting droplets of fluid at highspeed towards and onto the powder bed. Ejection of droplets can beperformed with utmost precision to predefined target place. By managingsize of droplets, amount of droplets and specific target place the exactplacement on and penetration depth in a substrate can be preciselycontrolled. Jet printing is well-known from inkjet printing technologybut in contrast to this technology the fluid that is printed in theprocess of the present invention is not an ink for printing of imagesbut a fluid that contains materials that are usable for printing ofsolid pharmaceutical administration forms, especially an energyabsorbing or reflecting material, a fusible material or an activeingredient.

The fluid used for jet printing is a liquid wherein the material to beprinted is distributed. Examples of liquids that can be used fordistribution of the material are water, organic solvents, such asethanol, or mixtures of both, whereby the organic solvent may be solublewith one another or not. The material may be dissolved, suspended oremulsified in the fluid. Auxiliaries such as surfactants may be used,e.g. to improve dispersibility of the material in the fluid and/orspreading or wetting of particles in the powder bed.

The term “energy absorbing material” as used herein means any materialthat absorbs IR, NIR, VIS, UV or microwave irradiation and converts itto some extend to heat. In principle, any energy absorbing material canbe used in the present invention. Energy absorbing materials that areespecially suitable for the present invention are carbon black, pigmentsand anorganic salts, e.g. oxides and salts and alloys of iron, zinc,magnesium, aluminium or other metals, organic dyes and liquids (e.g.water). Certain energy absorbing materials may further possess theproperty to reflect or scatter radiation, which may lead to an improvedheat distribution. Examples may include pigments of a certain particleshape and size, pigments with layered structures and interferencepigments such as composites comprising silicate minerals (such as sheetsilicate (phyllosilicate) minerals (mica) or potassium aluminiumsilicate) and oxides of titanium or iron (Candurin® pigments). Theenergy absorbing material can be used in any form and particle size thatis processable and that provides heat generation and distributionsuitable for running the process. The energy absorbing material can haveany particle size that is suitable to be processed in the process andthat is suitable to create the heat needed. For example, the energyabsorbing material can have a mean particle diameter from about 10 nm toabout 200 μm. When jetting the energy absorbing material, the preferredmean particle diameter can be about 10 nm to about 10 μm, preferablyfrom about 50 nm to about 5 μm, more preferably from about 100 nm toabout 2 μm. When including the energy absorbing material in the powder,the preferred mean particle diameter can be about 1 μm to about 200 μm,preferably from about 10 μm to about 100 μm, more preferably from about30 μm to about 70 μm.

The process as described above uses an energy absorbing material toprovide the heat that is necessary for melting and fusing of the fusiblematerial. However, depending on the melting point or glass transitiontemperature of the fusible material, the absorption spectrum ofcomponents of the powder bed and the amount of thermal energy providedby the irradiation, the irradiation alone can be sufficient to inducemelting and fusing of the fusible material so that the addition of anenergy absorbing material is not necessary. In this case jet printing ofan energy absorbing material can be replaced by jet printing of thefusible material.

Therefore, the present invention is also directed to a process for themanufacture of a solid pharmaceutical administration form comprising anactive ingredient comprising the steps

(a) spreading a powder comprising an active ingredient across themanufacturing area to create a powder bed;

(b) jet printing a fluid comprising a fusible material onto the powder;

(c) irradiating the powder to induce melting and fusing of the fusiblematerial present in the powder;

(d) spreading a layer of powder onto the surface of unfused and fusedpowder and subsequently performing step (b) and step (c);

(e) repeating step (d) as often as needed to build up the solidpharmaceutical administration form;

(f) separating the solid pharmaceutical administration form from thepowder bed.

In some instances, the processes described above may lead to so muchheat development that direct removal of the solid pharmaceutical dosageform from the powder bed after its manufacture causes damage of thesolid pharmaceutical dosage form, especially damage of its shape. Inthis case a cooling step is introduced between manufacturing of thesolid pharmaceutical dosage form and its removal from the mountingplate. Accordingly, the invention is also directed to a process for themanufacture of a solid pharmaceutical administration form as set forthabove, that is characterized in that a cooling step is introducedbetween steps (d) and (e).

The cooling step comprises any method that leads to sufficient reductionof the temperature of the solid pharmaceutical form to a temperaturevalue to assure that the shape of the solid pharmaceutical dosage for ismaintained when it is removed from the mounting plate. Examples of acooling step are simple remaining of the solid pharmaceutical dosageform on the mounting plate at ambient temperature until obtainingsufficient temperature reduction or active cooling, such as cooling by acold air flow. Preferably, the cooling step would allow to control thecooling rate and thus the physical characteristics of the quenched melt.

In some instances, the processes described above may lead to physicalchanges such as melting of the fusible material in places adjacent tothe intended region. Especially processes using materials with broadermelting or glass transition ranges or strong heat dissipation may beaffected by this phenomenon. Such processes may be improved byselectively cooling of the fusible material in places adjacent to theintended region. Such improvement may be achieved by using a partingagent. As used herein a “parting agent” refers to an agent thatfacilitates the shape and removal of the object of fused powder createdby the irradiation by minimizing or avoiding sticking of powder of thesurrounding powder bed to the object. Minimizing or avoiding of powdersticking to the object can be achieved by selective cooling of thesurrounding powder bed, preferably by evaporation cooling. Agents thatmay be used as parting agent comprise volatile fluids, preferablypharmaceutically acceptable solvents such as water, methanol or ethanol,liquid alkanes such as pentane, hexane or heptane, more preferably wateror ethanol.

By precise placement of the parting agent to the intended edges in thepowder bed shape accuracy and edge definition of the printed object canbe improved. The parting agent may further serve as means to modulatesurface or matrix porosity of the resulting dosage form.

In the process of the present invention precise placement of the partingagent can be easily realized by jet printing of the parting agent ontothe powder, either in parallel or subsequently in step (b). Accordingly,the invention is also directed to the process for the manufacture of asolid pharmaceutical administration form as set forth above, wherein instep (b) a parting agent is jet printed onto the powder in parallel orsubsequently.

In some instances, especially if an active ingredient has a rather lowmelting point or glass transition temperature that is comparable to thefusible material, for example, if it has a glass transition temperatureof at least 20° C. higher than the projected storage condition at thesame humidity, and/or if an active ingredient has energy absorbingproperties comparable to the energy absorbing material, it may befeasible that a solid pharmaceutical administration form can be formedby the process of the invention without the presence of a fusiblematerial or an energy absorbing material. In such instances the processof the present invention can be run without the presence of a fusingmaterial in step (a) or adding a fusible material by jet printing (stepb). Accordingly, the present invention is further directed to a processfor the manufacture of a solid pharmaceutical administration formcomprising an active ingredient comprising the steps

(a) spreading a powder comprising an active ingredient across themanufacturing area to create a powder bed;

(c) irradiating the powder to induce melting and fusing of the fusiblematerial present in the powder;

(d) spreading a layer of powder onto the surface of unfused and fusedpowder and subsequently performing step (b) and step (c);

(e) repeating step (d) as often as needed to build up the solidpharmaceutical administration form;

(f) separating the solid pharmaceutical administration form from thepowder bed.

In some instances, the speed of the processes described above may beimproved by pre-heating the build chamber, the powder bed or powdersupply with a suitable method without disrupting the powder bed. Thepowder may be heated to a temperature 2-50° C. below the melting pointor glass transition temperature of the fusible material at which thepowder bed still retains favorable flow properties. Accordingly, theinvention is also directed to a process for the manufacture of a solidpharmaceutical administration form as set forth above, whereinpre-heating is applied in steps (a) and (d) prior to or after spreadingthe powder.

The shape of the solid pharmaceutical dosage form can be easilydetermined by controlling the area of jet printing of either the energyabsorbing material or the fusible material to the powder bed. Uponirradiation in the first case the energy absorbing material heats upresulting in melting and fusing of the fusible material surrounding theenergy absorbing material and thereby forming a fused three-dimensionalnetwork layer. In the second case irradiation directly heats up thefusible material resulting in melting and fusing of the fusible materialthereby causing a fused three-dimensional network layer.

Any desired shape, such as rectangular, quadratic, cruciform, circular,ring (donut) or oval, can be achieved by operating the processes. Byassembling drug containing layers with different shapes solidpharmaceutical administration forms of any three-dimensional shape canbe easily obtained. Compared to conventional tablet production theprocess of the present invention provides wide flexibility with respectto the shape the solid pharmaceutical administration form.Advantageously the shape of the solid pharmaceutical administration formcan be easily adapted to various specific demands and, in addition,allows new shapes that cannot be made available by conventional tabletmanufacturing processes, such as, for example, a capsule filled withsolid powder.

The process of the invention can provide solid pharmaceuticaladministration forms with different dosages and/or different activeingredients in a flexible manner. For example solid pharmaceuticaladministration forms with different dosages but the same activeingredient can be manufactured by simply controlling the number of APIcontaining layers that are attached to one another. Solid pharmaceuticaladministration forms with the same active ingredient but differentrelease properties such as an administration form, wherein a part of theactive ingredient is released in an immediate release manner and anotherpart of is released in a sustained release manner, can be manufacturedby assembling active ingredient containing layers having immediaterelease properties and active ingredient containing layers havingsustained release properties. In a similar manner solid pharmaceuticaladministration forms with different active ingredients can be providedby successively creating layers comprising different active ingredients,wherein the different active ingredients are present as a mixture in theactive ingredient containing layer and/or wherein the different activeingredients is present in different active ingredient containing layers.The latter is preferred if the active ingredients are incompatible toeach other.

The source of irradiation used in the process can be infrared energy(IR), near-infrared energy (NIR), visible light (VIS), ultraviolet light(UV), microwave or X-radiation. Infrared energy is preferred. The sourceof irradiation used in the process can be diffuse (e.g. lamps, gasdischarge tubes) or focused (e.g. lasers). Therefore, the invention isfurther directed to a process that is characterized in that theirradiation is infrared energy (IR), near-infrared energy (NIR), visiblelight (VIS), ultraviolet light (UV), microwave or X-radiation,preferably infrared energy (IR).

Beside active ingredient and fusible material described above the powderused in the process of the invention can comprise further materials thatmay be necessary for the manufacture of a solid pharmaceuticaladministration form that fulfill the demands that are made on them suchas release properties of the active ingredient and storage stability ofthe solid pharmaceutical administration form. Such materials includeinert material or an additional functional material.

As used herein, “inert material” refers to any material that has amelting or glass transition temperature sufficiently above thetemperature that is achieved at running the process so that the shape ofthe inert material is remained during conducting of the process of theinvention. When used in the process of the present invention the inertmaterial provides structure to the solid pharmaceutical dosage form uponmelting and fusing of the fusible material, or other useful propertiessuch as improved powder flowability, improved disintegration ordissolution of the solid pharmaceutical application form. Examples of aninert material that may be used in the process of the present inventionsare silica, silicate minerals, sugars, starches, calcium carbonate,cellulose derivatives.

As used herein, “additional functional material” refers to any materialthat provides a function desired to be implemented into the solidpharmaceutical dosage form e.g. to control release profile of activeingredient. For example, release profile could be delayed by hydrophobicmaterial, which may act as diffusion barrier, by reducing wetting, ordelaying disintegration.

Another example of an additional functional material is a material thatprovides a functional coating around a core containing the API (e.g.enteric, taste-masking, moisture protective, oxygen protective). Thiscoating may be more protective than a classical capsule (which is madeof two parts and thus includes a slit).

In principle, the powder bed and/or the individual powder layer createdby one spreading step is either a homogenous or an inhomogeneous mixtureof a fusible material and other material, whereby upon irradiation thefusible material acts like a glue for the other material.

The structure of the solid pharmaceutical dosage form can bedistinguished into voxels. As used herein, “voxel” refers to thesmallest defined volume element that can be modified by the processespecially by the jet printing step and the irradiation step in aregular grid in three-dimensional space. As used herein, “voxel” canrefer to an individual element, which, in combination with other voxels,defines an intermediate element which is part of the three-dimensionalstructure. A particular voxel may be identified by x, y, and zcoordinates of a selected point of geometry of the shape, such as acorner, centre, etc.

In state of the art processes all voxels belonging to a structure arecompletely molten in the process to allow for a homogeneous appearance,cohesiveness and physical stability of the final structure. From abiopharmaceutical perspective, a completely densified structure (i.e.coherent and non-porous) is not preferred for a solid pharmaceuticaldosage form as it impairs the disintegration of the solid pharmaceuticaldosage for and the dissolution of the active ingredient. In commonpharmaceutical processes this problem is solved by the creation ofporous materials, e.g. by granulation or tableting. However, suchtechniques are not transferable to 3 D printing processes and remain tobe an obstacle for using such processes for the manufacture of solidpharmaceutical dosage forms.

Advantageously the process of the present invention allows to addressthis problem and to provide a solid pharmaceutical dosage forms thatmeets the requirements such as an appropriate dissolution of activeingredient or disintegration. Basis for this is that the process of thepresent invention allows the precise creation of well-defined voxelswith different properties in terms of solubility, swelling andmechanical stability.

The process of the present invention allows the manufacture or solidpharmaceutical dosage forms with specific structures that and thereby tocontrol the bioavailability of the active ingredient. It is well-knownthat the amorphous or crystalline state or the ad/absorption of anactive ingredient greatly influences its bioavailability. For example,solubilized and active ingredient (e.g. with organic solvents) can bejet printed on a powder base containing suitable inert or fusibleparticles which interact with the active ingredient in a desired manner,thereby e.g. preventing crystallization during evaporation of thesolvent/dispersing agent.

The invention is illustrated in the Figures.

FIG. 1 illustrate the spreading step (a) of the process. Onto a mountingplate (1) a powder provided by a powder reservoir (3 a) is spread bymoving a doctor blade (4) in the direction indicated by an arrow toachieve a powder layer. A part of the powder layer that is alreadyspread is indicated by (3). By repeating of the spreading of powder onthe already existing powder layer(s) as often as necessary a powder bed(2) is created.

FIG. 2 shows the powder bed (2) that is created by step (b) on themounting plate.

FIG. 3 shows jet printing in accordance to step (b) of the process. Amulti material jet (MMJ) (7) is moved along x and/or y axis thereby jetprinting a fluid (6) (in fine droplets) onto the powder bed (2). Suchjet printing results in powder soaked with fluid (5) created by voxelsthat are adjacent to one another. As indicated by the different colorsof the fluid droplets more than one fluid can be jet printed by the MMJ(7) depending on the process.

FIG. 4 shows the irradiation in accordance to step (c). A source ofradiation (SER) (11) is moved along x and/or y axis above the powdersoaked with fluid (5). Upon irradiation (10) by the SER the fusiblematerial present in the powder soaked with fluid fuses thereby creatinga layer of fused powder (9).

FIG. 5 shows the jet printing step as in FIG. 3 whereby the intermediateproduct shown in FIG. 4, onto which a layer of powder was spread, isused. In contrast to FIG. 3 the fluid is not jet printed on a continuousarea but on defined areas of the powder that are delimited from eachother so that a layer of powder voxels soaked with fluid (8) and powdervoxels without fluid (8 a) are created.

FIG. 6 shows irradiation as in FIG. 4 whereby the intermediate productshown in FIG. 5 is irradiated. Upon irradiation (10) by the SER thefusible material present in the powder voxels soaked with fluid (8) isfused thereby creating fused powder voxels (12) with adjacent unfusedpowder voxels. The fused powder voxels (12) are also fused with thelayer with the fused powder (9) thereby forming a mechanical stablethree-dimensional structure.

Depending on the desired structure of the solid pharmaceutical dosageform further layers can be added that may be completely fused powderlayer (9) or a layer comprising powder voxels that are fused (12),unfused (12 a) or partially fused (13). The voxels can be widely variedin their three-dimensional structure, such as their form and size, forexample by adaption of the fluid composition and precise control of thejet printing (e.g. amount of fluid, fluid droplet size or placement offluid droplet), and their distribution in an individual layer (createdby subsequent performing of steps (a), (b) and (c)) and/or in thethree-dimension network of the solid pharmaceutical dosage form.

Porous structures where only a part of the voxels are molten anddensified can be created. While the molten voxels ensure cohesiveness ofthe structure suitable for filling, handling, transportation of thesolid pharmaceutical dosage form without deformation or wear of frictionthe unmolten voxels support the disintegration upon contact with fluids(e.g. gastric, intestinal, water) by creating pores and channels for thefluid to penetrate the structure and create a larger surface fordissolution.

An example of such a structure is shown in FIG. 6 B, which is a hybridof unsolidified powder voxels and fused powder voxels. While the fused(solidified) voxel (9) provide mechanical stability the powder theunfused powder voxels (12 a) can freely dissolve.

FIG. 6 A shows another embodiment of this principle. In this embodimentunfused powder voxels (12 a) are surrounded by fused voxels (12) thatprovide envelopment of the unfused powder voxels and mechanicalstability. In this case, only the outer layer of the solidpharmaceutical dosage form is densified, while the core still consistsof loose powder, thereby creating something similar to a powder-filledcapsule.

FIG. 6 C shows an embodiment of another principle. In this case, allvoxels of a structure are treated in the same way, thus creating astructure which would be homogeneous on a macroscopic scale, butsomewhat heterogeneous on a microscopic scale. This can be achieved byfine tuning the energy exposure of a given voxel to achieve a voxeltemperature close to the melt or glass transition temperature of thepowder, e.g. by choosing a suitable amount of applied energy or appliedenergy absorber, in such a way that only a partial melting would beinduced. This would result in a continuous molten and densified phasewhich contains unmolten particulates as microscopic defects in anotherwise continuous structure.

A more robust process is achieved by premixing two or more componentswith different melt or glass transition temperatures. In this case thetemperature of a voxel does not need to be fine-tuned but controlled ina way that one component would melt, while another component wouldremain as unmolten particulates, again creating microscopic defectsbeneficial for disintegration and dissolution.

The process of the invention provides high flexibility how the materialsthat constitute the solid pharmaceutical dosage form are applied to eachother. In fact, the materials can be applied either as part of thepowder that is introduced by the spreading step or as part of a fluidthat is jet printed to the powder. In the following examples ofadvantageous embodiments of the inventions are illustrated wherein thematerials are applied in different ways.

FIG. 7 A shows an embodiment of the process, wherein the powder used instep (a) comprises an active ingredient (15), an inert material (16) anda fusible material (17) and the fluid used in step (b) comprises anenergy absorbing material (14). FIG. 7 B shows the same embodiment ofthe process as in 7 A, wherein the powder does not contain an inertmaterial (16).

FIGS. 8 A and B show embodiments of the process, wherein the powder usedin step (a) comprises an active ingredient (15) and an inert material(16). In FIG. 8 A shows an embodiment of the process, wherein the energyabsorbing material (14) and a fusible material (17) are present inseparate fluids that are jet printed in parallel, whereas in FIG. 8 Bshows an embodiment where the absorbing material (14) and a fusiblematerial (17) are present in and jet printed as one fluid.

FIG. 9 shows an embodiment of the process, wherein the powder used instep (a) comprises an inert material (16) and a fusible material (17)and wherein a fluid comprising an energy absorbing material (14) and afluid comprising an active ingredient are jet printed in parallel. Thisembodiment is especially suitable if a high precision is needed (e.g.highly potent active ingredient is used) and may also be useful toimpregnate porous materials with (amorphous) active ingredient, e.g.mesoporous silica. The energy absorbing material and the activeingredient may also be contained in the same fluid.

FIGS. 10 A to D are directed to embodiments of the process wherein thepowder used in step (a) comprises an inert material (16), a fusiblematerial (17) is not included. Instead jet a fusible material (17) isprinted together with an active ingredient (15) and an energy absorbingmaterial (14) either in one fluid or in different fluids in parallelthrough separate channels. This embodiment combines the formation of insitu solid dispersions (either due to melting, or due toco-precipitation of polymer and

API in a spray-drying like process) with melt granulation/drug productmanufacturing.

FIG. 10 A shows an embodiment of the process wherein an energy absorbingmaterial (14), an active ingredient (15) and a fusible material (17) arepresent in separate fluids that are jet printed in parallel.

FIG. 10 B shows an embodiment of the process wherein an energy absorbingmaterial (14) and an active ingredient (15) are present in one fluid anda fusible material (17) is present in another fluid and wherein bothfluids are jet printed in parallel.

FIG. 10 C shows an embodiment of the process wherein an energy absorbingmaterial (14), an active ingredient (15) and a fusible material (17) arepresent in and jet printed as one fluid.

FIG. 10 D shows an embodiment of the process wherein a fusible material(17) and an active ingredient (15) are present in one fluid and anenergy absorbing material is present in another fluid and wherein bothfluids are jet printed in parallel.

FIGS. 11 A to D are directed to embodiments of the process that do notuse an energy absorbing material. In such embodiments fusing takes placeonly in spots where the fusible material is jet printed.

FIG. 11 A shows an embodiment of the process wherein the powder used instep (a) comprises an active ingredient (15) and an inert material (16)and the fluid used in step (b) comprises a fusible material (17).

FIG. 11 B shows an embodiment of the process wherein the powder used instep (a) comprises an active ingredient (15) and the fluid used in step(b) comprises a fusible material (17).

FIG. 11 C shows an embodiment of the process wherein the powder used instep (a) comprises an inert material (16) and wherein a fluid comprisinga fusible material (17) and a fluid comprising an active ingredient (15)are jet printed in parallel.

FIG. 11 D shows an embodiment of the process wherein the powder used instep (a) comprises an inert material (16) and wherein a fluid comprisinga fusible material (17) and an active ingredient (15) are jet printed.

FIG. 12 shows an embodiment of the process where an additionalfunctional material (18) is used. In such embodiment the powder used instep (a) comprises an active ingredient (15), an inert material (16) anda fusible material (17) and separate fluids comprising either an energyabsorbing material (14) or an additional functional material (18) arejet printed in parallel.

The invention claimed is:
 1. A process for the manufacture of a solidpharmaceutical administration form comprising an active ingredientcomprising the steps (a) spreading a powder comprising a fusiblematerial and an active ingredient across a manufacturing area to createa powder bed; (b) jet printing a fluid comprising an energy absorbingmaterial onto the powder; (c) irradiating the powder to induce heatingof the energy absorbing material in the powder and thereby to inducemelting and fusing of the fusible material present in the powder; (d)spreading another layer of the powder onto the surface of unfused andfused powder and subsequently performing step (b) and step (c) again;(e) optionally repeating step (d) as often as needed to build up thesolid pharmaceutical administration form; (f) separating the solidpharmaceutical administration form from the powder bed.
 2. A process forthe manufacture of a solid pharmaceutical administration form comprisingan active ingredient comprising the steps (a) spreading a powdercomprising an active ingredient across a manufacturing area to create apowder bed; (b) jet printing a fluid comprising a fusible material ontothe powder; (c) irradiating the powder to induce melting and fusing ofthe fusible material present in the powder; (d) spreading another layerof the powder onto the surface of unfused and fused powder andsubsequently performing step (b) and step (c) again; (e) optionallyrepeating step (d) as often as needed to build up the solidpharmaceutical administration form; (f) separating the solidpharmaceutical administration form from the powder bed.
 3. A process forthe manufacture of a solid pharmaceutical administration form accordingto claim 1, wherein in step (b) a parting agent is jet printed onto thepowder in parallel or subsequently to the jet printing of the energyabsorbing material.
 4. A process for the manufacture of a solidpharmaceutical administration form according to claim 1, whereinpre-heating is applied in steps (a) and (d) prior to or after spreadingthe powder.
 5. Process according to claim 1, wherein a cooling step isintroduced between steps (e) and (f).
 6. Process according to claim 1,wherein the irradiating is with irradiation energy that is infraredenergy (IR), near-infrared energy (NIR), visible light (VIS),ultraviolet light (UV), microwave or X-radiation.
 7. Process accordingto claim 1, wherein in step (b) the fluid is jet printed more than oncein parallel or subsequent jet printings.
 8. Process according to claim1, wherein an active ingredient is jet printed in step (b) and whereinthe powder used in steps (a) and (d) does not comprise an activeingredient.
 9. Process according to claim 1, characterized in that thepowder used in step (a) of the process further comprises an inertmaterial.
 10. Process according to claim 1, characterized in that thepowder used in step (a) of the process further comprises an additionalfunctional material.
 11. Process according to claim 1, wherein theirradiating is with irradiation energy that is infrared energy (IR).